4IUF

Crystal Structure of Human TDP-43 RRM1 Domain in Complex with a Single-stranded DNA

Summary for 4IUF

• Entry DOI: 10.2210/pdb4iuf/pdb
• Descriptor: TAR DNA-binding protein 43, 5'-D(*GP*TP*TP*GP*(XUA)P*GP*CP*GP*T)-3' (3 entities in total)
• Functional Keywords: rna recognition motif, rna binding, dna binding, splicing factor, transcription regulator-dna complex, protein-dna complex, transcription regulator/dna
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q13148
• Total number of polymer chains: 2
• Total formula weight: 11866.19

Authors

Kuo, P.H.,Doudeva, L.G.,Wang, Y.T.,Yang, W.Z.,Yuan, H.S. (deposition date: 2013-01-21, release date: 2014-01-29, Last modification date: 2024-02-28)

Primary citation

Kuo, P.H.,Chiang, C.H.,Wang, Y.T.,Doudeva, L.G.,Yuan, H.S.
The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG- and TG-rich nucleic acids.
Nucleic Acids Res., 42:4712-4722, 2014

PubMed Abstract: TDP-43 is an important pathological protein that aggregates in the diseased neuronal cells and is linked to various neurodegenerative disorders. In normal cells, TDP-43 is primarily an RNA-binding protein; however, how the dimeric TDP-43 binds RNA via its two RNA recognition motifs, RRM1 and RRM2, is not clear. Here we report the crystal structure of human TDP-43 RRM1 in complex with a single-stranded DNA showing that RRM1 binds the nucleic acid extensively not only by the conserved β-sheet residues but also by the loop residues. Mutational and biochemical assays further reveal that both RRMs in TDP-43 dimers participate in binding of UG-rich RNA or TG-rich DNA with RRM1 playing a dominant role and RRM2 playing a supporting role. Moreover, RRM1 of the amyotrophic lateral sclerosis-linked mutant D169G binds DNA as efficiently as the wild type; nevertheless, it is more resistant to thermal denaturation, suggesting that the resistance to degradation is likely linked to TDP-43 proteinopathies. Taken together all the data, we suggest a model showing that the two RRMs in each protomer of TDP-43 homodimer work together in RNA binding and thus the dimeric TDP-43 recognizes long clusters of UG-rich RNA to achieve high affinity and specificity.

PubMed: 24464995
DOI: 10.1093/nar/gkt1407

Experimental method

X-RAY DIFFRACTION (2.752 Å)